The identification of tumor antigens in melanoma recognized by T cells has heralded a renewed interest in the use antigen-specific immunotherapy for the treatment of malignancies. Adoptive immunotherapy using antigen-specific T cell clones of defined specificity and phenotype with a high avidity for tumor cells represents in which the magnitude the effector population can be rigorously controlled. Thus adoptive therapy is a conceptually attractive strategy for manipulating the immune response so that requirements for effective antigen-specific therapy can be established. We have developed methods using peptide-pulsed APCs to isolate antigen-specific T cells from the peripheral blood and, peptide-MHC tetramers to rapidly select high avidity tumor-reactive CD4+ and CD8+ T cell clones. A clinical trial was conducted using adoptively transferred antigen-specific CD8+ T cell clones to evaluate the safety, duration of in vivo persistence and anti-tumor efficacy of infused T cells. This trial demonstrated that adoptive transfer of T cell clones was without significant toxicity and that T cells migrated to sites of disease and mediated an antigen-specific immune response; however, there was limited evidence of clinical regression. Potential obstacles to complete tumor eradication were identified. In the absence of helper function, such as IL-2, the in vivo survival of infused CTL was short with a half-life of less than 8 days and demonstrated a functional defect following antigen stimulation. It has been demonstrated that CD4 T cells alone can mediate an anti-tumor effect and the potential to overcome some of the observed limitations of using CD8 T cells. In this context, a Phase I clinical trial of adoptive CD4+ T cell therapy was designed to evaluate: 1) the safety, 2) the duration of in vivo persistence, and 3) the antitumor efficacy of adoptively transferred tyrosinase-specific CD4+ T cell clones for the treatment of patients with metastatic melanoma.